James Loudin

Photovoltaic retinal prosthesis with high pixel density

Retinal degenerative diseases lead to blindness due to loss of the “image capturing” photoreceptors, while neurons in the “image processing” inner retinal layers are relatively well preserved. Electronic retinal prostheses seek to restore sight by electrically stimulating surviving neurons. Most implants are powered through inductive coils, requiring complex surgical methods to implant the coil-decoder-cable-array systems, which deliver energy to stimulating electrodes via intraocular cables. We present a photovoltaic subretinal prosthesis, in which silicon photodiodes in each pixel receive power and data directly through pulsed near-infrared illumination and electrically stimulate neurons. Stimulation was produced in normal and degenerate rat retinas, with pulse durations from 0.5 to 4 ms, and threshold peak irradiances from 0.2 to 10 mW/mm2, two orders of magnitude below the ocular safety limit. Neural responses were elicited by illuminating a single 70 μm bipolar pixel, demonstrating the possibility of a fully-integrated photovoltaic retinal prosthesis with high pixel density.

Photovoltaic retinal prosthesis : implant fabrication and performance

The objective of this work is to develop and test a photovoltaic retinal prosthesis for restoring sight to patients blinded by degenerative retinal diseases. A silicon photodiode array for subretinal stimulation has been fabricated by a silicon-integrated-circuit/MEMS process. Each pixel in the two-dimensional array contains three series-connected photodiodes, which photovoltaically convert pulsed near-infrared light into bi-phasic current to stimulate nearby retinal neurons without wired power connections. The device thickness is chosen to be 30 µm to absorb a significant portion of light while still being thin enough for subretinal implantation. Active and return electrodes confine current near each pixel and are sputter coated with iridium oxide to enhance charge injection levels and provide a stable neural interface. Pixels are separated by 5 µm wide trenches to electrically isolate them and to allow nutrient diffusion through the device. Three sizes of pixels (280, 140 and 70 µm) with active electrodes of 80, 40 and 20 µm diameter were fabricated. The turn-on voltages of the one-diode, two-series-connected diode and three-series-connected diode structures are approximately 0.6, 1.2 and 1.8 V, respectively. The measured photo-responsivity per diode at 880 nm wavelength is ∼0.36 A W(-1), at zero voltage bias and scales with the exposed silicon area. For all three pixel sizes, the reverse-bias dark current is sufficiently low (<100 pA) for our application. Pixels of all three sizes reliably elicit retinal responses at safe near-infrared light irradiances, with good acceptance of the photodiode array in the subretinal space. The fabricated device delivers efficient retinal stimulation at safe near-infrared light irradiances without any wired power connections, which greatly simplifies the implantation procedure. Presence of the return electrodes in each pixel helps to localize the current, and thereby improves resolution.

Photodiode Circuits for Retinal Prostheses

Photodiode circuits show promise for the development of high-resolution retinal prostheses. While several of these systems have been constructed and some even implanted in humans, existing descriptions of the complex optoelectronic interaction between light, photodiode, and the electrode/electrolyte load are limited. This study examines this interaction in depth with theoretical calculations and experimental measurements. Actively biased photoconductive and passive photovoltaic circuits are investigated, with the photovoltaic circuits consisting of one or more diodes connected in series, and the photoconductive circuits consisting of a single diode in series with a pulsed bias voltage. Circuit behavior and charge injection levels were markedly different for platinum and sputtered iridium-oxide film (SIROF) electrodes. Photovoltaic circuits were able to deliver 0.038 mC/cm2 (0.75 nC/phase) per photodiode with 50- μm platinum electrodes, and 0.54-mC/cm2 (11 nC/phase) per photodiode with 50-μ m SIROF electrodes driven with 0.5-ms pulses of light at 25 Hz. The same pulses applied to photoconductive circuits with the same electrodes were able to deliver charge injections as high as 0.38 and 7.6 mC/cm2 (7.5 and 150 nC/phase), respectively. We demonstrate photovoltaic stimulation of rabbit retina in-vitro, with 0.5-ms pulses of 905-nm light using peak irradiance of 1 mW/mm2. Based on the experimental data, we derive electrochemical and optical safety limits for pixel density and charge injection in various circuits. While photoconductive circuits offer smaller pixels, photovoltaic systems do not require an external bias voltage. Both classes of circuits show promise for the development of high-resolution optoelectronic retinal prostheses.

Photovoltaic retinal prosthesis

Electronic retinal prostheses seek to restore sight to patients suffering from retinal degenerative disorders. Implanted electrode arrays apply patterned electrical stimulation to surviving retinal neurons, producing visual sensations. All current designs employ inductively coupled coils to transmit power and/or data to the implant. We present here the design and initial testing of a photovoltaic retinal prosthesis fabricated with a pixel density of up to 177 pixels/mm2. Photodiodes within each pixel of the subretinal array directly convert light to stimulation current, avoiding the use of bulky coil implants, decoding electronics, and wiring, and thereby reducing surgical complexity. A goggles-mounted camera captures the visual scene and transmits the data stream to a pocket processor. The resulting images are projected into the eyes by video goggles using pulsed, near infrared (~900 nm) light. Prostheses with three pixel densities (15, 55, and 177 pix/mm2) are being fabricated, and tests indicate a charge injection limit of 1.62 mC/cm2 at 25Hz. In vitro tests of the photovoltaic retinal stimulation using a 512-element microelectrode array have recorded stimulated spikes from the ganglion cells, with latencies in the 1-100ms range, and with peak irradiance stimulation thresholds varying from 0.1 to 1 mW/mm2. With 1ms pulses at 25Hz the average irradiance is more than 100 times below the IR retinal safety limit. Elicited retinal response disappeared upon the addition of synaptic blockers, indicating that the inner retina is stimulated rather than the ganglion cells directly, and raising hopes that the prosthesis will preserve some of the retinas natural signal processing.

Inner retinal preservation in rat models of retinal degeneration implanted with subretinal photovoltaic arrays.

Photovoltaic arrays (PVA) implanted into the subretinal space of patients with retinitis pigmentosa (RP) are designed to electrically stimulate the remaining inner retinal circuitry in response to incident light, thereby recreating a visual signal when photoreceptor function declines or is lost. Preservation of inner retinal circuitry is critical to the fidelity of this transmitted signal to ganglion cells and beyond to higher visual targets. Post-implantation loss of retinal interneurons or excessive glial scarring could diminish and/or eliminate PVA-evoked signal transmission. As such, assessing the morphology of the inner retina in RP animal models with subretinal PVAs is an important step in defining biocompatibility and predicting success of signal transmission. In this study, we used immunohistochemical methods to qualitatively and quantitatively compare inner retinal morphology after the implantation of a PVA in two RP models: the Royal College of Surgeons (RCS) or transgenic S334ter-line 3 (S334ter-3) rhodopsin mutant rat. Two PVA designs were compared. In the RCS rat, we implanted devices in the subretinal space at 4 weeks of age and histologically examined them at 8 weeks of age and found inner retinal morphology preservation with both PVA devices. In the S334ter-3 rat, we implanted devices at 6-12 weeks of age and again, inner retinal morphology was generally preserved with either PVA design 16-26 weeks post-implantation. Specifically, the length of rod bipolar cells and numbers of cholinergic amacrine cells were maintained along with their characteristic inner plexiform lamination patterns. Throughout the implanted retinas we found nonspecific glial reaction, but none showed additional glial scarring at the implant site. Our results indicate that subretinally implanted PVAs are well-tolerated in rodent RP models and that the inner retinal circuitry is preserved, consistent with our published results showing implant-evoked signal transmission.

Delivery of Information and Power to the Implant, Integration of the Electrode Array with the Retina, and Safety of Chronic Stimulation

The fundamental function of a visual prosthesis is to deliver information about a patient’s surroundings to his/her neurons, usually via patterned electronic stimulation. In addition to transmitting visual information from the outside world to the implanted stimulating array, visual prostheses must also pass the electrical power necessary for such stimulation from the external world to the intraocular electrode array. The first section of this chapter reviews three common methods for achieving this data and power transfer: direct wireline connections (suitable for research studies), inductively coupled coils, and photodiode-based optical systems which utilize the natural optics of the eye.

Enhanced Tearing by Electrical Stimulation of the Anterior Ethmoid Nerve

Purpose Electrical neurostimulation enhances tear secretion, and can be applied to treatment of dry eye disease. Using a chronic implant, we evaluate the effects of stimulating the anterior ethmoid nerve on the aqueous, lipid, and protein content of secreted tears. Methods Neurostimulators were implanted beneath the nasal mucosa in 13 New Zealand white rabbits. Stimulations (2.3–2.8 mA pulses of 75–875 μs in duration repeated at 30–100 Hz for 3 minutes) were performed daily, for 3 weeks to measure changes in tear volume (Schirmer test), osmolarity (TearLab osmometer), lipid (Oil-Red-O staining), and protein (BCA assay, mass spectrometry). Results Stimulation of the anterior ethmoid nerve in the frequency range of 30 to 90 Hz increased tear volume by 92% to 133% (P ≤ 0.01). Modulating the treatment with 50% duty cycle (3 seconds of stimulation repeated every 6 seconds) increased tear secretion an additional 23% above continuous stimulation (P ≤ 0.01). Tear secretion returned to baseline levels within 7 minutes after stimulation ended. Tear film osmolarity decreased by 7 mOsmol/L, tear lipid increased by 24% to 36% and protein concentration increased by 48% (P ≤ 0.05). Relative abundance of the lacrimal gland proteins remained the same, while several serum and corneal proteins decreased with stimulation (P ≤ 0.05). Conclusions Electrical stimulation of the anterior ethmoid nerve increased aqueous tear volume, reduced tear osmolarity, added lipid, and increased the concentration of normal tear proteins. Human studies with an intranasal stimulator should verify these effects in patients with aqueous- and lipid-deficient forms of dry eye disease.

Photovoltaic retinal prosthesis for restoring sight to the blind

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the developed world, with an incidence of 1:500 in patients aged 55–64, and 1:8 in patients over 85 [1]. Retinitis pigmentosa (RP) is an inherited disease blinding about 1 in every 4000 individuals much earlier in life [2]. In both of these conditions the photoreceptor layer degenerates, while the inner retinal neurons survive to a large extent [3–5]. Electrically activating these neurons provides an alternative route for visual information and raises hope for the restoration of sight to the blind. In a normal retina, photoreceptors convert light into neural signals that are processed by inner retinal neurons, leading to generation of action potentials in the retinal ganglion cells (RGCs). These signals travel to the brain through the optic nerve and serve as the basis for visual perception. Electrical stimulation of the retina with microelectrodes can also produce action potentials in RGCs, creating spatially patterned percepts of light called phosphenes. Indeed, recent clinical trials with retinal prosthetic electrode arrays have restored visual acuity to subjects blinded by retinal degeneration up to 20/1200 using epiretinal placement (facing the ganglion cell side) [6], and up to 20/550 with subretinal implantation [7]. While this serves as an important proof of concept with clinically useful implications, existing retinal prosthesis designs have a number of shortcomings.

Photovoltaic retinal prosthesis for restoring sight to the blind: implant design and fabrication

We have designed and fabricated a silicon photodiode array for use as a subretinal prosthesis aimed at restoring sight to patients who lost photoreceptors due to retinal degeneration. The device operates in photovoltaic mode. Each pixel in the two-dimensional array independently converts pulsed infrared light into biphasic electric current to stimulate remaining retinal neurons without a wired power connection. To enhance the maximum voltage and charge injection levels, each pixel contains three photodiodes connected in series. An active and return electrode in each pixel ensure localized current flow and are sputter coated with iridium oxide to provide high charge injection. The fabrication process consists of eight mask layers and includes deep reactive ion etching, oxidation, and a polysilicon trench refill for in-pixel photodiode separation and isolation of adjacent pixels. Simulation of design parameters included TSUPREM4 computation of doping profiles for n+ and p+ doped regions and MATLAB computation of the anti-reflection coating layers thicknesses. The main process steps are illustrated in detail, and problems encountered are discussed. The IV characterization of the device shows that the dark reverse current is on the order of 10-100 pA-negligible compared to the stimulation current; the reverse breakdown voltage is higher than 20 V. The measured photo-responsivity per photodiode is about 0.33A/W at 880 nm.

Neuromodulation for Treatment of Dry Eye

Abstract Dry eye, a multifactorial disease of the tears and ocular surface, leads to tear film instability, potentially resulting in tear film hyperosmolarity, ocular surface epithelial damage, and inflammation. Impaired visual-related function associated with dry eye disease poses a significant economic and humanistic burden worldwide. Current treatment options are mostly palliative in nature, intended to supplement tears and alleviate dry eye symptoms. Neuromodulation is an established therapeutic strategy utilizing the direct activation of neural pathways to correct organ dysfunction and manage disease symptoms. A novel intranasal tear neurostimulation device has been developed, designed to increase tear production and improve tear quality in patients with dry eye by activating the nasolacrimal neuronal pathway through electrical stimulation of sensory nerve endings in the nasal mucosa. In clinical studies, the intranasal tear neurostimulator has demonstrated ability to increase tear production and improve symptoms, showing promise as a treatment option for patients with dry eye.